Age-related maculopathy (ARM) is a complex eye disease of adults over age 50 that is the leading cause of irreversible vision impairment and blindness in the United States. There are approximately 14 million Americans with ARM with the vast majority of these individuals - 12 million -- having early disease. Even in the early stages of ARM, there is significant personal burden from the disease in that it causes difficulty in reading, driving, and working, (42, 43), depression, and an overall decrease in quality of life. At present, ophthalmologists and optometrists have nothing to offer patients with early disease to slow its progression, and there are no proven prevention strategies for those who are currently disease free yet at high-risk for its development. A barrier to developing treatments to prevent ARM is a poor understanding of the factors that bring about the emergence of the disease. Knowledge of these factors will improve our understanding of the underlying biological causes, which can then lead to the development of treatments to prevent the disease. Through the parent grant, we are conducting a prospective study to identify functional and structural retinal characteristics in older adults who appear to be in normal retinal health that are related to their later development of early ARM. We are asking what factors predispose the disease. We are particularly interested in whether deficits in rod photoreceptor function in the retina as revealed by a test called dark adaptometry can identify which patients are at high-risk for the eventual development of ARM. Previous research has established that rod photoreceptors are vulnerable to degeneration and dysfunction in the earliest phases of ARM, however these studies have been unable to address whether the rod photoreceptor dysfunction precedes the emergence of the disease. Our prospective study in the parent grant will allow us to address this question. Although the focus of the specific aims in the parent grant are on dark adaptation, the study is also measuring detailed aspects of visual function, retinal structural characteristics, and health and lifestyle characteristics at baseline, in addition to dark adaptation;all of these factors may influence one's susceptibility to ARM. Recent research has indicated that three additional factors -- inflammation, cholesterol, and genetics -- play a potentially significant role in ARM pathogenesis. However, the role of these factors has not been examined with respect to the transition from normal aging of the retina to early ARM. Our prospective study can be the first to evaluate this issue in a large sample of older adults having normal retinal health at baseline, who are then followed over time for the incident development of the earliest signs of ARM. In addition, inflammation, lipid, and genetic markers have not been studied in light of their interplay with the rich and detailed functional, structural, health, and lifestyle data collected on this older cohort. With this competitive revision, we are requesting support to collect and analyze data on inflammatory markers and lipid levels and to extract DNA from participant blood samples from the older adults in this cohort for later genetic study, as well as immortalize cell lines as a back-up. Together the data from the parent grant and the competitive revision can go far in improving our understanding of how these factors influence an older adult's susceptibility to this blinding disease so that preventive treatments can be developed. PUBLIC HEALTH RELEVANCE: Age-related maculopathy (ARM) is the leading cause of irreversible vision impairment in older adults in the U.S. and many other countries. This research program is designed to shed light on factors that predispose the normally aging retina to develop into early ARM. This study is specifically focusing on the roles of inflammation, cholesterol, and the potential for genetic markers in contributing to the development of the disease. This information could lead to ways to prevent ARM and arrest its early progression.